Human beings are unique when compared with species because of their enlarged brain and
highly developed cognitive ability. It is known that even compared with our closely-related
relatives, the non-human primates, we have much larger brain size and more sophisticated
cognitive skills. It has become a common wisdom that the large brain of humans is the
consequence of adaptive evolution, i.e. positive Darwinian selection. But until now, little is
known about the genetic mechanism why we have enlarged brain and highly developed
cognition. Previous studies have shown that several genes related to brain development have
undergone positive selection during human origin. Other studies pointed out that the
evolution of human brain may also have something to do with the change in the regulation of
gene expression. Therefore, searching for genes differentially regulated between human and
non-human primate may shed more light on this issue.
MicroRNAs(miRNAs) are a class of noncoding RNAs that can post-transcriptionally
regulate the expression of protein coding genes in metazoans. By regulating the expression of
their target genes, miRNAs participate in various physiology courses. It has been reported
that the expression of many brain expressed miRNAs fluctuates during brain development.
This implies that miRNAs play an important role in brain development, and changes of the
interactions between miRNAs and their target genes may have effects on brain development.
In this study, we focus on miRNAs preferentially expressed in brain and conserved among
mammalian species. Through target gene prediction and comparative sequence analysis in
representative mammalian species, we identified that several predicted target genes have
human specific mutations in the target sites located in their 3’UTR segments. We speculate
that these human specific mutation sites may change the efficiency of regulation between
miRNAs and their target genes. And this change may contribute to the evolution of human
brain. Using in vitro reporter gene system, we found that several predicted target genes were
real targets of the corresponding miRNAs. Among them, one of the miR-127 target genes,
SEMA3F, contains a human specific mutation in the target site which reinforces the
interaction between miR-127 and SEMA3F. Mutation of this human specific site backwards to that of chimpanzee reduces the interaction between miR-127 and SEMA3F to the level of
chimpanzee. This result demonstrates that in vitro, the human specific mutation can alter the
interaction between miR-127 and SEMA3F. But more experiments are needed to confirm
whether it also works in vivo.
In conclusion, through in vitro reporter gene system, we found that sequence variations in
the 3’UTR segment of miRNA target gene may have functional consequence. And it might be
one of the important genetic mechanisms which are pivotal for the origin and evolution of
human brain.
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